Critical role of guanylate binding protein 5 in tumor immune microenvironment and predictive value of immunotherapy response.

Background: The guanylate-binding proteins (GBPs) are the latest potential targets of immunotherapy. However, the role of GBP5 in pan-cancer, including colorectal cancer (CRC), remains unclear. This study aims to explore the effect of GBP5 on immunity in pan-cancer. Methods: Based on the RNA sequencing data of 33 cancers obtained from The Cancer Genome Atlas, we analyzed the clinical significance of GBPs and focused on the correlation between GBP5 and tumor microenvironment (TME). Immunotherapy cohort IMvigor210 was used to explore the relationship between treatment response and GBPs. Then, we further analyzed the expression of GBP5 in immune cells using single-cell transcriptome cohort GSE146771 and GSE132465 from the Gene Expression Omnibus database. Finally, a prognostic model based on GBP5 expression was established and validated. Results: We found that the expression of GBP3/4/5 is higher in colorectal cancer than in normal tissues, and GBP5 is a better predictor of good treatment response to immune checkpoint blockade than other GBPs. In most other cancers, GBP5 is also elevated in tumors compared with normal tissues and is associated with a better prognosis. As for TME, GBP5 is generally positively correlated with immune score, the level of tumor-infiltrating immune cells and immune-related genes. Single-cell analysis showed that GBP5 was mainly expressed in myeloid cells and T cells. The GBP5-related prognostic model we constructed in CRC can predict the survival of patients and propose some genes for subsequent research. Conclusion: This study revealed a strong correlation between GBP5 and immunity in generalized cancer and provided evidence that CRC may be a suitable cancer type for anti-GBP5 therapy.

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma.

BACKGROUND AND AIM: Lipid metabolic reprogramming is considered to be a new hallmark of malignant tumors. The purpose of this study was to explore the expression profiles of lipid metabolism-related genes (LMRG) in colorectal cancer (CRC). METHODS: The lipid metabolism statuses of 500 CRC patients from the Cancer Genome Atlas (TCGA) and 523 from the Gene Expression Omnibus (GEO GSE39582) database were analyzed. The risk signature was constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression. RESULTS: A novel four-LMRG signature (PROCA1, CCKBR, CPT2, and FDFT1) was constructed to predict clinical outcomes in CRC patients. The risk signature was shown to be an independent prognostic factor for CRC and was associated with tumour malignancy. Principal components analysis demonstrated that the risk signature could distinguish between low- and high-risk patients. There were significantly differences in abundances of tumor-infiltrating immune cells and mutational landscape between the two risk groups. Patients in the low-risk group were more likely to have higher tumor mutational burden, stem cell characteristics, and higher PD-L1 expression levels. Furthermore, a genomic-clinicopathologic nomogram was established and shown to be a more effective risk stratification tool than any clinical parameter alone. CONCLUSIONS: This study demonstrated the prognostic value of LMRG and showed that they may be partially involved in the suppressive immune microenvironment formation.

Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer.

Background: As a heterogeneous disease, colorectal cancer (CRC) presents a great challenge to individualized treatment due to its lymph node metastasis (LNM). Existing studies have shown that immune and stromal components in extracellular matrix (ECM) act as important part in tumorigenicity and progression, while their roles in LNM have not been fully elucidated. Here, crucial ECM-related genes responsible for LNM in CRC were selected by multi-omics analysis. Methods: Firstly, we characterized the immune infiltration landscape of CRC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases by using ssGSEA algorithm. The CRC patients were divided into several immune subgroups by hierarchical clustering analyses. Then, differential genes were identified among immune subgroups and CRC vs. normal tissues in TCGA and GEO GSE39582 cohorts, respectively. Next, weighted correlation network analysis (WGCNA) was employed to construct a co-expression network to find LNM-related modules and hub genes. Subsequently, we evaluated the clinical value of hub gene in prognostic prediction and chemotherapy/immunotherapy. Besides, the protein level of key gene was verified in an external cohort from our center. Finally, we explored the underlying mechanism of FSTL3-mediated LNM by Gene function annotation and correlation analysis. Results: Two immune subgroups, namely Immunity_High and Immunity_Low, were defined among the two CRC cohorts using ssGSEA algorithm, respectively. Based on the two immune subgroups, 2,635 overlapping differentially expressed genes were obtained from two cohorts, which were sequentially subjected to WGCNA and univariate Cox regression analysis. Ultimately, FSTL3 was selected as the key gene. Here, we first confirmed that overexpression of FSTL3 correlated with LNM and worse prognosis in CRC and was verified at the protein level in the external validation cohort. Moreover, FSTL3 expression showed strongly positive correlation with immune and stromal components in ECM. We furthermore found that FSTL3 may accelerate LNM through the formation of inhibitory immune microenvironment via promoting macrophage and fibroblast polarization and T cell exhaustion. Interestingly, high FSTL3 expression is linked to chemoresistance, but immunotherapy-sensitive. Conclusion: FSTL3 is identified as a biomarker for ECM remodeling and worse clinical outcomes for the first time in CRC and is also a potential immunotherapeutic target to block LNM for CRC.

Role of ferroptosis-related genes in prognostic prediction and tumor immune microenvironment in colorectal carcinoma.

BACKGROUND AND AIM: Colorectal cancer (CRC) ranks the second most common cause of cancer-related mortality worldwide. Ferroptosis, a recently discovered form of programmed cell death different from other, raises promising novel opportunities for therapeutic intervention of CRC. This study intended to systematically assess the prognosis value and multiple roles of the ferroptosis-related genes in the tumor immune microenvironment of CRC. MATERIALS AND METHODS: Of 1,192 CRC patients with complete information from the public datasets (TCGA CRC, GEO GSE39582 and GSE17538 cohorts) were selected for analysis. Firstly, K-means consensus clustering was performed to identify ferroptosis-associated subtypes in CRC patients. Subsequently, we constructed a risk signature based on ferroptosis-related genes in TCGA cohort and acquired its validation in two GEO cohorts. Additionally, we established a nomogram integrating the risk signature and clinical factors to improve risk assessment of CRC patients. RESULTS: Five molecular subtypes were identified by consensus clustering for ferroptosis-related genes. There were significant differences in the overall survival, immune cells infiltration status and PD1/PD-L1 mRNA among the five clusters. Then, a risk signature based on the ten-gene was constructed which could distinguish effectively high-risk group among CRC patients in both training and validation sets. The high-risk patients were more likely to have an inhibitory immune microenvironment and lower stemness features. A prognostic nomogram integrated risk signature and clinicopathological features could be used as a more accurate prognostic prediction visualization tool than TNM stage alone. CONCLUSION: This ferroptosis risk signature may accurately differentiate between different risk populations and predict the prognosis of CRC. Besides, this study elucidated the crucial role of ferroptosis in tumor immune microenvironment.

CAR-T cells for Colorectal Cancer: Target-selection and strategies for improved activity and safety.

Chimeric antigen receptor-T (CAR-T) cell immunotherapy is a novel method that is genetically engineered to recruit T cells against malignant disease. Administration of CAR-T cells has led to progress in hematological malignancies, and it has been proposed for solid tumors like colorectal cancer (CRC) for years. However, this method was not living up to expectations for the intrinsic challenges posed to CAR-T cells by solid tumors, which mainly due to the lacking of tumor-restricted antigens and adverse effects following treatment. New approaches are proposed to overcome the multiple challenges to alleviate the difficult situation of CAR-T cells in CRC, including engineering T cells with immune-activating molecules, regional administration of T cell, bispecific T cell engager, and combinatorial target-antigen recognition. In this review, we sum up the current stage of knowledge about target-selection, adverse events like on/off-tumor toxicity, the preclinical and clinical studies of CAR-T therapy, and the characteristics of strategies applied in CRC.